AUGUSTA, Ga. - For estrogen replacement to provide stroke protection, it likely must be given soon after levels drop because of menopause or surgical removal of the ovaries, scientists report in the Journal of Neuroscience.

Animal studies indicate a "critical period" for estrogen replacement and that when therapy is delayed, estrogen receptors on brain cells are significantly diminished along with the neuroprotection estrogen typically conveys, according to scientists from the Medical College of Georgia, North China Coal Medical University and the University of Texas Health Sciences Center at San Antonio.

"We looked at the controversy over whether estrogen is going to be beneficial after long periods without it and found the answer appears to be 'no,'" says Dr. Darrell W. Brann, chief of MCG's Developmental Neurobiology Program and the study's corresponding author.

The controversy he's referencing resulted from the Women's Health Initiative, a 12-year study of 161,808 women ages 50-79 that examined the health benefits of hormone replacement therapy. Among the surprising findings was that estrogen and estrogen plus progesterone therapies, actually increased stroke risk rather than reduced it. Critics said one problem with the study was that many of the women had gone years without hormone replacement.

The animal studies indicate that they may be right, at least in terms of estrogen's ability to protect the brain. The studies focused on the hippocampus, a center of learning and memory, where scientists showed that estrogen was strongly protective against stroke in rats that got estrogen one week after surgical removal of their ovaries. When replacement therapy was delayed by 10 weeks after removal - equivalent to a couple of years of human life - estrogen was essentially useless.

A closer examination of the rats who went 10 weeks without estrogen showed alpha receptors, believed to mediate neuroprotective effects of estrogen, were decreased by 50 percent or more.

"That is why the receptors could not respond," says Dr. Brann, who also is associate director of MCG's Institute of Molecular Medicine and Genetics. "That seems to the fit the data that there is something estrogen is doing that is necessary to maintain the receptor at the proper levels."

Interestingly estrogen receptors were still intact and receptive in the uterus, another important estrogen target. "We are trying to figure out why there is a tissue difference," Dr. Brann says.

But inside the brain, there were other signs of collateral damage from estrogen deficits. CA3, an area of the hippocampus that tends to be stroke resistant, became vulnerable to stroke in rats that went long term without estrogen. "Estrogen must be doing something that is very critical for the protection of CA3 and we think it's suppressing NADPH oxidase production," Dr. Brann says. NADPH oxidase, the enzyme which makes the free radical superoxide, is found in high levels in the nearby CA1 region, but in low levels in CA3. Both regions, he notes, are critical to learning and memory.

When a stroke happens, estrogen helps suppress free radical production in CA1, which can become deadly to cells at further increased levels. The studies showed CA1 and CA3 regions were equally vulnerable to stroke in animals that went long periods without estrogen.

"If this is also true in humans, just using surgical menopause as an example, most women would be fine unless they came upon a severe stress," Dr. Brann, noting that stress could be not just a stroke but even severe emotional stress or simple aging. It may also explain why women who undergo surgical menopause are at increased risk of cognitive loss and dementia. "That is what we are thinking based on this data," Dr. Brann says.

Next steps include studying the state of estrogen receptors in the brains of naturally older rats - equivalent to about age 70 in humans - to see what happens with normal age-related estrogen loss, waiting a while, then putting estrogen back to see if there is any benefit.

They also want to examine the neuroprotective benefits of estrogen made locally in the brain compared with that made by ovaries, the largest estrogen source. In the past decade, scientists have learned that neurons and the supportive glia cells in the brain locally produce estrogen via the enzyme aromatase. Both men and women have estrogen receptors in the brain and the scientific consensus is that men's brains also produce estrogen.

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